The human multi-drug resistance (MDR1) gene makes a protein called P-glycoprotein (P-gp). P-gp may limit the absorption of medications including HIV protease inhibitors. HIV protease inhibitors are drugs used to treat people with HIV infection (the virus that causes AIDS). It is possible that the particular type of MDR1 gene that a person possesses (their genotype) influences the extent that P-gp limits the absorption of HIV protease inhibitors. The purpose of this study is to see how the MDR1 genes that each person got from his or her parents might affect how well he or she absorbs the protease inhibitors indinavir and saquinavir. This study will screen 150 healthy volunteers to determine their MDR1 genotype; 60 of these volunteers will receive saquinavir (10 doses) and indinavir (4 doses) and blood will be collected afterward to see whether MDR1 genotype influences the blood levels of these HIV medicines. Study subjects will also receive a single dose of midazolam to measure the activity of a particular enzyme (CYP3A) that is involved in breaking down saquinavir and indinavir in the body. To date, 41 subjects have been enrolled in this study. Preliminary findings among 38 evaluable subjects suggest that saquinavir absorption may be enhanced in individuals with a particular MDR1 genotype (TT at positions 3435 and 2677). As such, these data suggest that MDR1 genotype may influence saquinavir exposure. Further study will determine the importance of these findings in HIV-infected patients. In addition, the relationship between midazolam concentration and indinavir pharmacokinetics has been assessed in 11 of the subjects. CYP3A phenotype, determined using a single midazolam concentration, significantly correlated with indinavir oral clearance (R = 0.7; P =.016) and exposure (R = 0.644; P = .033) in these individuals. In addition, indinavir oral clearance was significantly higher in subjects with midazolam concentrations below, versus above, the median midazolam concentration (0.436 vs 0.238 L/hr/kg; P = .0019). In contrast, preliminary data from 37 evaluable subjects suggest that saquinavir pharmacokinetics do not correlate with CYP3A phenotype using oral midazolam as a metabolic probe. While these results are ancillary to the primary objective of this investigation, they are the first to show a significant relationship between CYP3A phenotype and protease inhibitor (indinavir) pharmacokinetics.